Abstract: Disease processes underlying development of End Stage Renal Disease (ESRD) in Type 1 Diabetes (T1D) are manifested by a relentlessly progressive renal decline that begins while renal function is normal. Despite significant gains in detailed knowledge of the process's manifestations, greater knowledge of its underlying mechanism(s) is desperately needed so new interventions to interrupt or retard it early can be developed. Reliable biomarkers that reflect early renal decline are needed to assess the effectiveness of interventions implemented at the early stage of renal decline. The development of high throughput technologies to analyze biospecimens creates opportunities to identify novel biomarkers that reflect disease progress very closely and, therefore, may serve as surrogates for ESRD as the endpoint. Moreover, the physiologic nature of such specific biomarkers of the processes underlying early progressive renal decline may point to new therapeutic targets. In the 1st stage of this proposal we will employ the high-throughput platform SOMASCAN which measures 1129 proteins to identify candidate proteins in plasma using specimens from well-characterized T1D patients who were followed for 8-15 years in the Joslin Proteinuria Study (P.I. AS Krolewski).The specific aims for this stage are: 1). Perform global proteomic analysis using SOMASCAN measurements in serial plasma specimens obtained during the initial 2-4 years follow-up of the Joslin Proteinuria Study (200 patients and 600 measurements); 2). Calculate changes in each protein and identify for which proteins the change differs between decliners and non-decliners. Then, for the subset of proteins that differed, evaluate among the decliners the relation between the change and 1) time to onset of ESRD and 2) long-term eGFR slope. From this we can determine which protein changes are sufficiently predictive to be candidates surrogate end-points. In the 2nd stage of this proposal will seek to validate the protein changes that emerge from the 1st stage (8-12 proteins) as candidate surrogate end-points in the 3-year PERL clinical trial, which aims to evaluate the effectiveness of Allopurinol in preventing/slowing GFR loss in T1D. Specific aims for this stage are: 1). In plasma from the 250 patients enrolled in the placebo arm, we will assay (ELISA/LUMINEX) the concentration of proteins identified in the 1st stage using samples obtained at 0, 18, and 36 months. The correlation of a protein's change with the GFR slope determined during the trial by serial measurements of iohexol clearance (iGFR), a gold standard measure of renal function, will measure its potential as a surrogate for measured renal function. 2). In plasma from the 250 patients enrolled in the Allopurinol arm of the trial, we will repeat the procedure performed in placebo patients. Comparison of a protein's change in treated and placebo patients will measure the effect of Allopurinol on it as a surrogate end-point and reveal how accurately the effect of Allopurinol treatment on GFR loss could be determined by the putative surrogate end-points.